Help!

I am looking around for a specific indicator for ferric ions that's very specific for ferric over ferrous. It should be water soluble and stable at room temperature and neutral or basic pH. In addition, it should be very sensitive and should be able to detect slight increases in ferric concentration by a bright colour change. And of course, the colour change should be easily detectable by a spectrophotometer, or more preferably, by the human eye.

Help will be much appreciated!

Please, save science from the "holists"

There are two kinds of environmentalists. One kind which is a scarce breed consists of the ones who are willing to do cost-benefit analysis and apply rational scientific thinking based on available facts to suggest policy. The other kind, sadly even now the majority, are against nuclear power, are not averse to hijacking oil tankers to make their point, and are more concerned about the fate of koala bears than about prudent science-based solutions to climate change. These environmentalists often, but not always, include far-left anti-corporate activists. Many of them tout "holistic farming" and vague notions of glorified "scientific solutions" to the world's food, medical and environmental problems. Most jarringly, they hold many scientists in contempt and subscribe to the strange postmodernist view of science, wherein science is "just another way of looking at reality".

Vandana Shiva, who has a PhD. in physics from the University of Western Ontario, is unfortunately one of them.

Sovietologist brings one of her crazier articles to my attention. According to Shiva, the traditional reductionist approach to science is not only incorrect but responsible for the deaths of thousands of people. Shiva thinks that the reductionist approach has harmed science and essentially should be side-lined and abandoned in favour of a more generalized "holistic" approach. Thrown out of the window are the benefits to billions that reductionist science has brought.

According to Shiva,

"In order to prove itself superior to alternative modes of knowledge and be the only legitimate mode of knowing, reductionist science resorts to suppression and falsification of facts and thus commits violence against science itself, which ought to be a search for truth. We discuss below how fraudulent this claim to truth is."

Shiva then helpfully rails against every application of science from medicine to agriculture to energy. I don't think it's even worth discussing the many glaring flaws and rampant cherry picking in her ramblings, but her opinions of medicine especially rankled me

Simple ailments have been cured over centuries by appropriate use of concoctions made from plants and minerals found in nature. 'Scientific medicine' removes the diversity by isolating 'active' ingredients or by synthesizing chemical combinations. Such processing first involves violence against the complex balance inherent in natural resources. And then, when the chemical is introduced into the human body, it is often a violation of human physiology.

Little does Shiva realize that by obfuscating the issue and presenting medical therapy as a "violation of human physiology" she is obscuring the fact that that's what precisely any foreign substance introduced in the body does. And by the way, perhaps Shiva has forgotten the billions of lives that "active ingredients" have saved all over the world. She gives the example of the psychoactive drug reserpine isolated from the beautiful flowering plant Rauwolfia serpentina. It was perhaps the first drug that brought dignity and benefits to countless patients of psychoses. Then, it began showing unacceptable side effects. But Shiva not only does not stress the benefits, but stops here. There is no discussion of scores of future anti-psychotic drugs which were focused on reducing these side-effects and improving efficacy. Even today we don't have the perfect drug for schizophrenia, but intense efforts continue in both academia and industry. For Shiva these efforts are trivial and even misguided.

Not surprisingly then, Shiva launches into an litany of benefits for "natural" concoctions. As with other extreme propaganda, there is a shred of truth to this contention. There is no doubt that many Ayurvedic medicines bring real benefits. However, there is merit to isolating the active ingredient from any such natural source and modifying it to reduce toxicity. That is how most drugs have been developed, by starting from an isolated natural molecule and then tuning its properties to reduce toxicity and improve potency. Shiva needs to educate herself a little about the process of drug discovery.

However, Shiva's real agenda, hidden all along, becomes clear at the end. If postmodernist leanings don't move you, compassionate socialist ones surely will:

But it is highly unlikely that medical science and pharamaceutical establishments will pay heed. For the reductionist medical science cannot but manufacture reductionist products and undermine the balance inherent in natural products. The multinationals that produce synthetic drugs in pursuit of fabulous profits and ignore their toxic side effects do not care. When they are forbidden to sell some harmful drugs in the home countries, they find a lucrative market in the third world, where the élites, including the medical establishment, are usually bewitched by anything that is offered as scientific, especially if it comes wrapped in pretty pay-offs. They give a free hand to multinationals to buy medicinal plants at dirt-cheap rates and sell the processed pills in the third-world countries at exorbitant prices and at enormous cost to the health of the people. The élites cannot accept that it would be more equitable socially, cheaper economically, conductive to self-reliance politically, and more beneficial medically for the third-world countries to use the plants locally according to time-tested indigenous pharmacology.

While multinational drug companies and the third-world political élites are out for profits, the third-world intellectual élites, eager to prove their scientific temper, join in a chorus to denounce indigenous therapeutics and related knowledge systems as hocus-pocus and their practice as quackery. It is through this mixture of misinformation, falsehood and bribes that a reductionist medical science has established its monopoly on medical knowledge in many societies.

That's right. The billions of lives that have been saved by the "elitist" multinational drug corporations are nothing compared to the virulent and rampant capitalism they have have infected third world populations with. If it's a private corporation, then by default it must be part of a global conspiracy to oppress poor people in developing countries.

As noted before, Shiva's entire essay contains too much cherry picking, straw man arguments and misleading information to criticize here. And again, Shiva tugs at the fine line between some legitimate objections to reductionist science and a full-blown irrational attack on its methods. We don't need Shiva to tell us that reductionist methods have their limitations; consider the recent emergence of fields like systems biology where scientists are trying to grapple to get a better perspective on overcoming these limitations. But no serious scientific critic of reductionist science will deny the immense benefits that it has served us since the dawn of humanity. Almost all the fruits of scientific research that we enjoy have come from reductionist science, and that will continue to be so. Disparaging wholesale the benefits of reductionist science and deriding the huge windfall of discoveries that reductionist science had bequeathed to us is a tremendous insult to the very edifice of scientific discovery. But then that's the standard agenda of the postmodernist-socialists; to contend that science is "just another way" of looking at reality and to charge scientists with having a "monopoly over the truth".

I have a simple suggestion for Shiva which I am sure she would not be loathe to accept. Next time she suffers from a deadly pathogenic infection, she should not take any antibiotic or drug manufactured by the evil companies. She should subsist on coconut water, isabgol and curd to ward off her illness. Shiva would then be truly walking the talk. Not only would she be proving her point about reductionist science doing her more harm than good and about antibiotics simply being one way among many to "look at reality", but her admirable bed-ridden efforts would be a true slap in the face of those evil multinational drug companies.

Whose fault is it, again?

Don't let your view of the Bush administration color your picture of reality

Usually I find myself vigorously nodding my head when I read most New York Times Op-Eds and columns. I share the Times's disdain for the Bush administration's policies and usually think they are right on spot when they criticize them. But in this particular case, I think they have let their rightly justified Bush-phobia lead to an unreasonable response.

The story is painful but straightforward. A woman was given the widely prescribed anti-nausea drug Phenergan by injection. When it did not work, the doctor opted for a riskier procedure during which his assistant accidentally punctured an artery in the woman's arm. Gangrene set in, and her entire right arm and hand tragically had to be amputated. Sneezing from a few allergies is hardly worth losing an arm.

The woman rightly sued the physician and his assistant and received a healthy out-of-court settlement. But then she also sued Wyeth, the drug's manufacturer. Why? For "failing to warn the clinicians to use the much safer “IV drip” technique, in which the drug is injected into a stream of liquid flowing from a hanging bag that already has been safely connected to a vein, making it highly unlikely that the drug will reach an artery". The trial court even awarded her a whopping 6.7 million dollars worth of damages. The NYT supports the court's decision and objects to Wyeth's displeasure:

Now Wyeth, supported by the Bush administration, has asked the Supreme Court to reverse the verdict on the grounds that Wyeth complied with federal regulatory requirements.

We do not buy Wyeth’s argument that it did everything it needed to, or could have done, to warn doctors about the dangers involved in the treatment Ms. Levine received. Wyeth did warn of some dangers of the drug treatment, in words approved by the F.D.A., but the state court was well within its rights to conclude that those warnings were insufficient.

So let me get this straight. Wyeth is being sued because the physician did not know what was the safest and best protocol to use and because his assistant botched up the operation?

In fact here's the shocker. Wyeth does have a strong warning against such an injection on its label.

"Under no circumstances should PHENERGAN Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene"

What more do you want the company to do? Emphasize "under no circumstances" three times? Were they also supposed to say, "Do not inject this drug directly into the heart"? I find this case outright bizarre.

Somehow the NYT also ties this event to the Bush administration's argument that companies should be protected from lawsuits if the FDA has completely approved their drug and the way it's prescribed. If anything, shouldn't the FDA be sued for not making sure that the company had all the warnings adequately written on the label here? I share the NYT's general contempt for industry-protecting Bush policies. But in this case the policy seems to make sense to me. If the FDA is supposed to be the "decider" when it comes to approving drugs, why should companies bear the brunt of failed drugs if the FDA has already approved them?

It is sad when general opinions that are justified lead to specific views that are not.

Selective vs Multitargeted Kinase Inhibitors: Still in the Stone Age

In the conference on kinase inhibitors I attended recently, there was a panel discussion on the second morning (why do these discussions have to start at 7:30 a.m.?) about the utility of selective vs multi- target directed inhibitors. The conventional wisdom has been that selective inhibitors- or any selective drugs for that matter- are best, since off-target effects can cause toxicity. The fight against cancer has largely been about finding selective and therefore safe drugs that hit targets only in cancer cells. It is a measure of how less we have accomplished in cancer therapy in spite of the countless amounts of dollars spent that we still are far from rationally designing reliable, selective and safe cancer drugs.

The discussion we had did not end in any consensus. While selective drugs may clearly be good in certain cases, there are cases in which drugs designed for selectivity ended up promoting their action by being non-selective and targeting multiple targets, but only in retrospect. Gleevec, the revolutionary drug for treating chronic myeloid leukemia, is a classic example. Initially supposed to be a "magic bullet" that targeted only a mutated kinase named Bcr-Abl in cancer cells, Gleevec later turned out to also potently target two other kinases, c-Kit and PDGFR. Interestingly these two targets are valuable targets in cancer therapy of two other cancers, renal cell carcinoma of the kidneys and glioblastoma of the brain.

In any case, the consensus was that we are still far away from designing drugs for a specifically chosen subset of targets. Something like staurosporine that hits almost every kinase out there is going to be undoubtedly gratuitously toxic. But inhibitors hitting a very specific subset of kinases could target a few crucial choke-points in disease pathways, thus serving as valuable drugs. But we are still far from rationally designing such inhibitors. Indeed, in the first place we don't even know what specific subset of kinases to hit for treating a particular disease. First comes target validation, then modulation. Most of the specific subset targeting kinase inhibitors seem to be discovered only in retrospect. In my own project where we are trying to target only one kinase selectively, we are now being skeptical about whether the beneficial effects we are observing are due to multi-target binding.

The other unrelated point we discussed was whether anybody knew kinase inhibitors which were near clinical trial phase completion for areas other than oncology. The silence around the table spoke for itself.

The bottom line is; as far as targeting specific subsets of kinases with inhibitors or even knowing which specific subset to target is concerned, we are still in the Stone Age of kinase drug discovery. The drugs which we have are largely still stone and tree branches. We have a long way to go before discovering tools and bronze.

In the next post, I will talk about a recent effort that overcame the rational multi-kinase inhibitor design for two very different kinases. It points the way forward.

History

Image: New York Times

Till I was about 13 or 14 years old, my readings of American history consisted only of offerings from the history of the United States during World War 2, an old and enduring historical interest of mine. It was when I picked up Harold Evans's The American Century, a superb and magisterial illustrated history of the country during the twentieth century, that I became painfully and woefully aware of the injustice that African-Americans faced in this country for two hundred years. I was horrified to read about Jim Crow, the dog squads and water hoses on the streets of Montgomery, Alabama, the lynchings in Mississippi. As a boy who was about the same age then, I was especially sickened and completely shaken by the relatively recent story of Emmet Till, a story that has been vividly seared into my mind ever since.

I could not believe that this was the country enshrined in the Declaration of Independence, the land which first and foremost looked at the integrity of one's character and his or her abilities and not where he or she came from. And yet I saw hope and fundamental human decency in Martin Luther King and the Civil Rights movement. But since then, I have often felt whether any event or moment in the United States could possibly mentally transport me to a pre-Harold Evans time when I had a singularly auspicious and pristine perception of this country. Such a moment would never come because one cannot erase the scars inflicted on this country's character for two hundred years. But I feel convinced that if there would be a moment closest to such a moment in my life, that moment would be yesterday night.

At midnight, I stood on the 15th floor of the Hyatt Regency Hotel and amid the car horns constantly blaring on the street downstairs, I strained my ears to catch every word that he spoke on the TV screen. The overriding feeling among everyone around me was one of peace and relief and tears even more than elation.

He looked tired, relieved and happy but not jubilant. He knows the difficult task that lies ahead and knows that celebration right now is premature. He knows that there's much to be done and that this is just the beginning. He knows that he may not be able to bring about a sea change in the way things have been done. But he knows that he will nudge the country in the right direction by valuing and fostering rationality and honest debate. He knows he will be upfront and forthright about what he thinks and he understands the value of the journey, even if the final destination may not be known. He understands the value of incremental progress.

And he knows that his extraordinary story culminating in yesterday's night healed at least some of the internal divisions among his own people and will go a long way in reviving his country's image in the world as the land of opportunity, diversity and respect.

He did it. Now we have to do it. Now we can get back to our lives.

Save Science on Tuesday

It was Richard Nixon who got rid of the Presidential Science Advisory Committee during his tenure, which has not been resurrected since. In the 80s, Ronald Reagan embraced the idealistic vision of Star Wars, a pipe dream that did not have a valid scientific basis. In the 90s, Congress got rid of the Office of Technology Assessment which is supposed to provide the country's political leaders with bipartisan scientific advice. Science on the whole in the last twenty five years has been on a downhill path as far as respect for it in political circles has been concerned.

Although George Bush's administration has been the single-largest malefactor of science and all it stands for and in general although Republicans have done more damage to science, all administrations since the 1970s have overall been lax and negligent in supporting science and its essential spirit. As I have written before, the issue goes far beyond the important one of providing funding for basic scientific research. It has to do with trusting unbiased advice that tries to give you a picture of the world as it is, and not how you would like to see it. It has to do with promoting and respecting open-mindedness and true bipartisan debate. Thus science has always stood opposite dogma, a fact that is usually hard to swallow for most politicians who would want to color the world with their own ideological brush. This is a wholly fatalistic attitude because a disrespect for science means an abandonment of informed decision making, eventually a sure path for a country's spiral into regress.

Barack Obama is not good for science because he is a liberal Democrat. He is good for science because he largely stands for all that science traditionally has; open minds, patient and careful thought, forthcomingness and respect in listening to dissenting opinions, a mistrust of blind reliance on authority and a willingness to listen to all sides of the debate before taking an informed decision. Obama also knows he is not perfect and embodies another key aspect of science; the ability to understand one's deficiencies and limitations and seek the best possible advice to overcome them. There is scarce doubt that he will bring knowledgeable science advisors into the White House and that he will take seriously the advice of people with whom he may not agree. At the same time he will weigh all the options and sides and try to take as unbiased a decision as he can. In an age of climate change, evolution, food crises, energy crises, drug resistance and nuclear terrorism, science is going to become an increasingly key and vocal part of the national debate and the future of this country. Obama understands this. Maybe that's why, a few days ago, 76 Nobel Prize winners represented by the great physicist Murray Gell-Mann wrote an open letter to the American people and endorsed Obama as most prudent for science in this country.



The American people need to reclaim their lost preeminence in science and technology and their respect for learning and rationality. They need to reaffirm their place in the world as the land where open minds meet unlimited resources and intellectual capital. The time has come when this land needs to save science from itself. With this in view, anyone who deeply cares about science, reason and objective thought should vote for Barack Obama on Tuesday.